This invention relates to novel methods, combinations, and compositions for controlling inflammation in the relief of symptomatic, chronic and acute rheumatic conditions. More particularly, the invention relates to combinations and compositions of indomethacin or phenylbutazone and phenoxymethyl-2-oxazolidinones and methods of using them to ameliorate the undesirable side effects of indomethacin or phenylbutazone in the gastrointestinal tract.
Indomethacin and phenylbutazone are widely used for the therapy of inflammatory conditions associated with rheumatic diseases and/or arthritis. However, certain undesirable side effects are associated with the use of indomethacin and phenylbutazone in the gastrointestinal region, among which side effects are bleeding, ulceration, perforation of the intestines and occasionally death. The need to overcome the irritation, particularly in the lower gastrointestinal tract, caused by indomethacin and phenylbutazone is a matter of urgent concern, inasmuch as the walls of the intestine in the lower region are relatively thin and perforation may occur suddenly and without warning. The method of the present invention, having suitably overcome, by remedial action, the severe manifestation of ulceration and perforation in the lower GI tract normally associated with indomethacin and phenylbutazone therapy, is highly suited to the treatment of the symptomatic inflammatory effect in mammals and humans of diseases such as gouty arthritis, bursitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and the like.
Indicative of the state of the art have been attempts to find combinations which would allow administration of indomethacin or phenylbutazone for their full therapeutic effect as anti-inflammatory drugs. Certain steroids such as spirolactone have shown protection against intestinal ulcers caused by indomethacin in rats [Can. J. Physiol. Pharmacol. 1969, 47 (12) 981-3]. Coprecipitates of lignosulfonate or tannic acid with indomethacin or phenylbutazone have shown reduced irritation on the stomach tissue of cats. [C. A. 78, P102009n and C. A. 79, P9873]. Pro-Bathine which is ammonium (2-hydroxyethyl)-diisopropylmethylbromide, xanthine-9-carboxylate has shown reduced ulceration caused by indomethacin in the rat stomach [Arch. Int. Pharmacodyn. 191, 370-377 (1971)].
Cyclobenzaprine has been combined with indomethacin or phenylbutazone for muscle relaxant effects (French Pat. No. 2,121,529). The dosages of indomethacin and phenylbutazone required are alleged to be less than the dosages normally required for effectiveness, and because less of these drugs are used side effects are reduced. In the instant invention these drugs are the phenoxymethyl-2-oxazolidinones which are administered for their anti-inflammatory effects act in the presence of normal dosage amounts of indomethacin and phenylbutazone to reduce incidence of intestinal bleeding, ulceration, perforation and death. Furthermore, muscle relaxation due to the phenoxymethyl-2-oxazolidinones in the combinations and compositions of this invention is not a prerequisite for accomplishing the reduction of side effects as the method of the invention has been demonstrated in animals at dosages which did not cause muscle relaxation to occur.